Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. This combined TLR/CD40 immunization generates CD8+ T cell responses even in CD4-depleted or CD4-deficient hosts. We have substantiated our previous hypothesis and have further observations which suggest an involvement of CD27 in regulating that activity of the transcription factor Blimp-1, the levels of which subsequently control the presence or absence of CD8+ T cell memory. Based on these results, this proposal will test the hypothesis that protective, CD4-independent CD8+ T cell immune memory requires a shift in the balance of the Blimp-1/Bcl-6 regulatory axis within CD8+ memory T cells (6, 7), a shift requiring the participation of the TNF receptor superfamily members CD27 and/or OX40 via CD70/OX40L expressing DCs. We will examine whether combined TLR/CD40-agonist immunization elicits CD4-independent CD8+ T cell memory by engaging the CD27/OX40 TNF receptors on antigen specific T cells, leading to the suppression of Blimp-1 expression in the T cell via Bcl-6 or an as yet undetermined molecular mechanism.